Additive for a powder material intended for compaction into shaped bodies

ABSTRACT

The invention relates to an additive for a powder material intended for compaction into shaped bodies. The additive is used to influence the powder material with regard to its cohesion and slidability on foreign surfaces and comprises as the main constituent one or more polyglycerol fatty acids, each obtained by way of a complete or partial esterification of a linear or branched polyglycerol containing two to eight glyceryl units with one or more fatty acids, each containing 6 to 22 carbon atoms.

When manufacturing pharmaceuticals, and also when manufacturing foodsupplements, there is frequently a need to compress powdered componentsinto shaped articles which are usually cylindrical in shape and arelargely used as tablets. In other industrial fields as well, shapedarticles are produced from powders; an example is in the detergentindustry. Requirements in the pharmaceutical industry are particularlystringent because here, a reproducible release of the pharmaceuticalmaterial has to be guaranteed, along with a sufficient breaking strengthand low abrasion of the shaped article. Moreover, they are produced inlarge numbers and the ability to compress the powder to be compresseduniformly on rapid rotary presses is demanded, wherein the pressingtools must neither be damaged by superfluous shear forces, nor candissolving the shaped article at the point of use be compromised. Inaddition, uniform feeding of the powder intended for compression isindispensable to smooth running of a rapid succession of compressionprocesses. However, this can only be regularly successful when thepowder is sufficiently free-flowing and does not form any agglomerateswhich could result in problems w the feeding and it being brought to ahalt.

In order to obtain a rapid, effective and uniform mechanical compressionprocess with good results and simultaneously with optimized machinedowntimes and maintenance cycles for worn parts, it has become standardpractice to add what are known as lubricants as an additive to powdersintended for compression, which lubricants reduce both the mutualcohesion of the powder components and also the adhesion of the powder toextrinsic surfaces without, however, the properties of the shapedarticle formed from the powder as regards wettability and consistencybeing affected too greatly. The use of magnesium distearate, C₂₆H₇₀MgO₄,abbreviated to MgSt, has been shown to be particularly advantageous. Asan alternative, for example, polyethylene glycols, abbreviated to PEGs,or glyceryl dibehenate, may also be used, wherein the latter is used asa mixture of mono-, di- and tri-esters of behenic acid which containsonly the diesters as the main component. Alternatives to MgSt aretherefore in great demand because incompatibilities can occur with somepowders containing pharmaceuticals, for example when they contain theantiviral acyclovir, the anticoagulant clopidogrel, the antihypertensivecaptopril, the antibiotics erythromycin or penicillin or the analgesicacetylsalicylic acid. Even the antidiabetic metformin, which is used inits water-soluble form as metformin-HCl, is potentially incompatiblewith MgSt, because it can be hydrolysed and can react with the MgSt,which is a Lewis acid, in the presence of residual moisture. PEGs, forexample, are not compatible with the most widely used anti-inflammatoryibuprofen or with clopidogrel, mentioned above. Regarding thealternative lubricant glyceryl dibehenate, it is not always possible toobtain optimal results as regards the properties of the shaped articles.The powders which are provided for compression into shaped articles, asdisperse systems of the “solid in gas” category, may consist of not onlythe solid particles, with particle sizes of less than 500 μm, but mayalso include larger components, for example pre-granulated components.

Thus, the objective is to provide other alternatives to theaforementioned lubricants which can provide comparably good results, inorder to provide alternatives in the case of problems withincompatibility or quality when using conventional lubricants. Thisobjective is achieved by means of additives according to claim 1,wherein advantageous selections of such additives are defined in thedependent claims 2 to 11, by means of compressed material composed ofpowder and additive according to claim 12, wherein advantageouscompressed materials are defined in the dependent claims 13 to 17, bymeans of a process according to claim 18, in which an additive accordingto one of claims 1 to 11 is used and by means of shaped articlesaccording to claim 19, which have the advantageous properties defined inclaims 20 to 23.

Surprisingly, it has now been shown for the first time that additiveswhich, according to claim 1, have polyglycerol fatty acid esters,abbreviated to PGFEs, as the major component, are highly suitable forinfluencing the cohesion and lubrication on extrinsic surfaces of apowder intended for mechanical compression into shaped articles as analternative to MgSt when such PGFEs are used, which each can be obtainedfrom a complete or partial esterification of a linear or branchedpolyglycerol containing two to eight glyceryl units with one or morefatty acids respectively containing 6 to 22 carbon atoms.

The simplest polyglycerols which can form the starting materials for anexpedient esterification are linear and branched diglycerols with theempirical formula C₆O₅H₁₄, which can be synthesized on an industrialscale and in a known manner, for example by reacting glycerol with2,3-epoxy-1-propanol under basic catalysis with the formation of etherbonds, or by thermal condensation under base catalysis, wherein thefraction containing mainly diglycerols can subsequently be separated.

Diglycerols can occur in three different structurally isomeric forms,namely in the linear form, in which the ether bridge is formed betweenthe respective first carbon atoms of the two glycerol moleculesinvolved, in the branched form, in which the ether bridge is formedbetween the first carbon atom of the first and the second carbon atom ofthe second glycerol molecule employed, and in a nucleodendrimeric form,in which the ether bridge is formed between the respective second carbonatoms. In the case of the condensation of two glycerol moleculescatalysed by an alkali, up to approximately 80% occurs in the linearform and up to approximately 20% in the branched form, while only a verysmall quantity of the nucleodendrimeric form is produced.

In the case of esterification with fatty acids, polyglycerols containingmore than two glyceryl units may also be used. In general, thepolyglycerols are abbreviated to “PG” and an integer n is added as asuffix, which provides the number of polyglyceryl units, i.e. “PG_(n)”.As an example, triglycerols are written as PG₃ and have the empiricalformula C₉O₇H₂O. Complete esterification with a fatty acid, for examplewith stearic acid, should now take place at all of the free hydroxylgroups of the PG_(n) molecule. In the case of a linear PG₃, then thiswould take place at the first and second carbon atoms of the firstglyceryl unit, at the second carbon atom of the second glyceryl unit andat the second and third carbon atoms of the third glyceryl unit. Theempirical formula for this example is therefore given as C₉O₇H₁₅R₅,wherein each R represents a fatty acid residue, in the selected examplewith the empirical formula C₁₈OH₃₅.

However, the established abbreviation for polyglycerols esterified withsaturated unbranched fatty acids is the designation PG(n)-Cm full esteror, as appropriate, PG(n)-Cm partial ester, wherein the “n” inparentheses, in similar manner to the designation for the polyglycerols,gives the number of glyceryl units contained in the molecule and mrepresents the number of carbon atoms of the saturated fatty acid usedfor the esterification reaction. Thus, the “n” represents the number ofglyceryl units with the empirical formula C₃O₂H₅R or C₃O₃H₅R₂ formarginal glyceryl units, wherein R may represent a fatty acid residue orthe hydrogen atom of a free hydroxyl group. “PG(2)-C18 full ester” wouldtherefore describe a polyglycerol fatty acid full ester with theempirical formula C₇₈O₉H₁₅₀ as the major component. In the case of thePG partial ester, the number of fatty acid residues is averaged,whereupon at the same time, the empirical formula provides the fractionwith the esterification variation which is present in the majority. Amore precise designation of the polyglycerol fatty acid partial ester isprovided by additionally providing the hydroxyl value, which is ameasure of the non-esterified hydroxyl group content and thus providesinformation regarding the degree of esterification of the partial ester.Presumably for steric reasons, the esterification reactions in this caseoccur preferentially from the outside to the inside. Thus, initially,the hydroxyl groups which are esterified are those which allow the fattyacid residue the highest degree of freedom. The first esterificationreaction at a linear polyglycerol then preferentially takes place at thehydroxyl group of a first carbon atom of a marginal polyglyceryl unit,then the second esterification reaction takes place at a hydroxyl groupof the third carbon atom of the marginal polyglyceryl unit at the otherend. Next, the hydroxyl groups at carbon atom positions immediatelyadjacent to positions which have already been esterified are esterified,and so on.

The term “fatty acids” as used here should be understood to meanaliphatic monocarboxylic acids containing 6 to 22 carbon atoms, whichare preferably unbranched and saturated and have an even number ofcarbon atoms, but they may also contain an odd number, or be branchedand/or unsaturated. Preferably, for the esterification of the PGFEs usedas the major component of the additive, fatty acids which are saturatedand/or unbranched are used. More advantageously, unbranched, saturatedfatty acids containing 16, 18, 20 or 22 C atoms are used for theesterification, i.e. palmitic, stearic, arachidic or behenic acid.

Advantageously, the PGFEs of this type which are of use are those which,when the PGFEs or individual PGFE is/are investigated using heat fluxdifferential scanning calorimetry, during the investigation, uponheating up, have only one endothermic minimum and upon cooling down, hasonly one exothermic maximum, because the pressing force of 10 kN andmore on the compressed material which is normally employed forcompression means that increased temperatures may arise which, whenunsuitable additive components are used, could lead to their polymorphictransformation and to properties of the shaped article which aredifficult to control. Additional polymorphic forms would be able to bedistinguished upon investigation using differential scanning calorimetryby the appearance of a local exothermic maximum upon heating the sampleup, as well as a local endothermic minimum upon cooling the sample down.The “blooming” that occurs after some time in storage in which thepolymorphism of a component causes a substantial increase in volumewhich is macroscopically visible, can be avoided by using additiveswhich exhibit no polymorphism. In particular, triglycerides such asglycerol tripalmitate or glycerol tristearate may have polymorphisms,i.e. respectively both a crystalline unstable a-modification as well asa metastable b′-modification or a stable b-modification may be presentand transform from one into the other modification. In this regard, themodifications differ in particular in the thickness of the lamellar,packed crystalline subunits which are also described as subcellularunits. As an example, for the a-modification of glycerol tristearate,under specific conditions, stacking of an average of 6 lamellarstructures per subcellular unit could be detected and after completetransformation into the b-modification, stacking of an average of 10.5lamellar structures per subcellular unit and an increase in the crystalthickness of approximately 67% was observed. Because in this case, thecomputed expected increase of 75% is not obtained, this is presumed tobe due to the fact that the individual lamellae of the b-modificationhave a denser lamellar packing because of the inclined position comparedwith the a-modification (see D G Lopes, K Becker, M Stehr, D Lochmann etal., in the Journal of Pharmaceutical Sciences 104: 4257-4265, 2015).

Because the additives remain in the final product, it is alsoadvantageous for the PGFEs which are used to have a stable subcellularform below their solidification temperature at 40° C. and 75% relativehumidity for at least 6 months, i.e. under the storage conditions for anaccelerated stability test, an essentially constant thickness of thelamellar-structured crystallites evaluated by employing small angle Xray scattering, abbreviated to SAXS, and applying the Scherrer equation.SAXS enables conclusions to be drawn regarding the size, the shape andthe internal surfaces of crystallites. The thickness of the respectivecrystallites can be calculated here using the Scherrer equation, whichis D=Kλ/FWHM cos (θ). Here, D designates the thickness of thecrystallites and K the dimensionless Scherrer constant, which enablesthe shape of the crystallites to be predicted and as a rule, to a goodapproximation, it can be taken to be 0.9. FWHM stands for “full width athalf maximum”, i.e. the width of the peak of an intensity maximum athalf the height above the background, measured in radians, and θ is theBragg angle, i.e. the angle of incidence of radiation onto the latticeplane. While a sample of glycerol tripalmitate stabilized with 10%polysorbate 65 has a crystallite thickness of 31 nm after storage forsix months at room temperature, corresponding to seven lamellae, and thecrystallite thickness after storage for six months at 40° C. is 52 nm,corresponding to 12 lamellae, is almost double, the aforementionedpolyglycerol fatty acid esters usually exhibit crystallite thicknessesof 20 to 30 nm, corresponding to 2 to 4 lamellae, and are stable aftersix months storage at 40° C., with the modifications unchanged. Incontrast, polyglycerol full esters usually exhibit a slightly highercrystallite thickness of 30 to 40 nm, indicating a higher degree oforganisation, corresponding to 5 to 8 lamellae, and are also stable withunchanged modifications under the storage conditions of an acceleratedstability test.

It is also advantageous if, when the PGFEs are used under the statedconditions, the lamellar separation according to an evaluation of theBragg angle using wide angle X ray scattering, abbreviated to “WAXS”, issubstantially constant. Individual investigations of the proposedpolyglycerol fatty acid esters below their respective solidificationtemperature using WAXS exhibit one maximum intensity for allpolyglycerol fatty acid esters which have been investigated, which meansthat a respective deflection angle of 21.4°, corresponding toapproximately 20, i.e. double the Bragg angle, can be deduced, whichgives a separation of the lattice planes of 415 μm, which correlateshere with the lamellar packing density of the molecules underinvestigation. This distance can be structurally associated with thea-modification in which the respective lamellar structures are disposedin a hexagonal lattice parallel to each other with molecules stacked oneach other and forming planes. Other modifications cannot be identified.The stability of the identified a-modifications was observed both atroom temperature and also at 40° C. for 6 months, also using WAXS. Hereagain, surprisingly, exclusively the respective polyglycerol fatty acidesters under investigation exhibited stable a-modifications.

For the preparation of the additives, PGFEs from the following group arepreferably selected: PG(2)-C18 full esters, PG(2)-C22 partial esterswith a hydroxyl value of 15 to 100, PG(2)-C22 full esters, PG(3)-C16/C18partial esters with a hydroxyl value of 100 to 200, PG(3)-C22 partialesters with a hydroxyl value of 100 to 200, PG(3)-C22 full esters,PG(4)-C16 partial esters with a hydroxyl value of 150 to 250, PG(4)-C16full esters, PG(4)-C16/C18 partial esters with a hydroxyl value of 150to 250, PG(4)-C16/C18 full esters, PG(4)-C18 partial esters with ahydroxyl value of 100 to 200, PG(4)-C22 partial esters with a hydroxylvalue of 100 to 200, PG(6)-C16/C18 partial esters with a hydroxyl valueof 200 to 300, PG(6)-C16/C18 full esters, PG(6)-C18 partial esters witha hydroxyl value of 100 to 200, wherein in the polyglycerol fatty acidesters containing two fatty acid residues which are different because ofthe number of their carbon atoms, those with a lower number are presentin an amount of 35% to 45%, those with a corresponding, complementaryhigher number are present in an amount of 55% to 65% and the specifiedfull esters preferably have a hydroxyl value of less than 5.

An advantageous property of the PGFEs for an additive in accordance withclaim 1 which should be considered is the hydrophobicity, which can bedetermined by determining the contact angle. The determination of thehydrophobicity is carried out by determining the contact angle betweenthe PGFE in the solid physical state and a droplet of purified water.According to Young's equation, cos θ=(γ_(SV)−γ_(SL))/γ_(LV), whereinγ_(SL) is the interfacial tension between the PGFE and water, γ_(LV) isthe interfacial tension of the water droplet and γ_(SV) is the surfacetension between the PGFE and the surrounding air. θ is the contactangle. Thus, the larger the contact angle θ, the higher is the surfacetension between the PGFE and the water and the higher is thehydrophobicity of the PGFE under investigation. The contact angles forthe proposed polyglycerol fatty acid esters also correlate with the HLBvalue which is often used in pharmaceutical technology, which is on ascale of 0 to 20 and provides information regarding the ratio oflipophilic to hydrophilic molecular fractions, wherein the hydrophilicfraction increases with increasing HLB value. For the compression of apowder comprising one or more pharmaceutical substances, the contactangle of the PGFEs used as the additive under storage conditions shouldundergo only moderate changes, so that the stability of the releasekinetics of the pharmaceutical substance or substances produced from thefinished shaped article is not compromised. Thus, preferably, thosepolyglycerol fatty acid esters which have a contact angle with water at40° C. and also at 20° C. after 16 weeks which deviates by less than 10°from the starting value are preferably used as the major component ofthe additive. As an example, glycerol tristearate has a comparativelyhigh contact angle deviation with water of 40° under the statedconditions and therefore deviates from the desired release kineticsstability; this can be attributed to a transformation from the a- intothe b-modification during storage. The solidification temperature forthe PGFEs used as additives is preferably below 75° C., but above 40° C.Here, the solidification temperature is defined as the value for thetemperature at which the maximum of the highest exothermic peak of theheat flux occurs during analysis of a sample using differential scanningcalorimetry.

Because of the conditions for their synthesis, PGFEs are always mixturesof different molecules, in particular in the case of partial esters. Itis, however, also possible for a suitable additive in accordance withclaim 1 to be provided after synthesis by mixing those PGFEs which canrespectively be obtained by esterification reactions which are differentbecause different reaction partners or different reaction conditions areemployed.

The size of the particles of additive has an influence on the totalsurface area of the additive, and therefore on the properties of thecomposition formed by the powder for compression and the additive. Inprinciple, it has been shown to be advantageous for the particle size ofthe additive to be 1 to 300 μm, preferably 5 μm to 15 μm.Correspondingly, the proportion of additives in the composition also hasan influence on their behaviour when mechanically compressing intoshaped articles and should advantageously not exceed 5% by weight;preferably, it is only 0.05% to 0.5% by weight. Too much additive isassociated with increased hydrophobicity of the composition and couldhave negative effects on the wettability of the prepared shaped article;its dissolution behaviour could then be slowed down in an undesirablemanner.

For applications in the pharmaceutical industry, the compressed materialformed from the powder provided for mechanical compression into a shapedarticle and the additive comprises at least one pharmaceuticalsubstance, such as metformin-HCl, for example. The term “pharmaceuticalsubstance” should be understood to mean both directly pharmacologicallyeffective substances and also substances which are only effective afterin vivo transformation into an active form. In addition, the powderpreferably contains microcrystalline cellulose as a filler; theproportion of this in the compressed material enables the volume of theshaped article to be controlled.

It has been shown to be advantageous for the compressed material formedfrom the additive and the powder to have only 0.05% to 0.5% by weight ofadditive and 99.5% to 99.95% by weight of powder, wherein the additiveconsists of a mixture of respectively 50% by weight of PG(3)-C22 fullester and PG(3)-C22 partial ester with a hydroxyl value of 100-200 orentirely of PG(3)-C22 partial ester with the same hydroxyl value. Inaddition to the additive, the compressed material may also contain aproportion of 15% by weight of metformin-HCl, for example, and aproportion of 84.5% to 84.95% by weight of microcrystalline cellulose.

For an optimized action of the additive as regards the influence on thecohesion and the lubrication on extrinsic surfaces for a powder intendedfor mechanical compression into shaped articles, prior to compression,preferably, before being fed to the compression site, the additive ispreferably mixed with the powder. This is because correct feeding to thecompression site in a shaped article compressing machine, as a rule intothe die of a tablet press, is also critically dependent on the flowproperties of the powder which are influenced by the additive in amanner such that the feed of the compressed material occurs uniformlyand without stoppages.

Furthermore, removal of the prepared shaped article from the respectivemould is a process which can only be carried out without problems whenthe composition of the shaped article guarantees a sufficientlubrication on extrinsic surfaces. Thus, the shaped article should havethe same composition as the compressed material and during compressionand the supply of energy associated therewith, should not undergo anychemical changes. This is of advantage if the force required forejecting the shaped article is no more than 150% of the ejection forcewhich is required under otherwise identical conditions for a test shapedarticle in which at least 40% by weight of the additive has beenreplaced by MgSt and the remainder optionally by the filler employed,preferably microcrystalline cellulose. In order to determine theejection force, values for 20 shaped articles are averaged each time.

During compression of the compressed material composed of additive andpowder by means of a rotary press, in the final step of the compressionprocess, the upper punch is forced onto the compressed material lying onthe lower punch, while in this step, the lower punch is moved in thedirection of the upper punch. The specific maximum pressure at the upperpunch for the respective compression process is thus transferred to acertain extent onto the lower punch via the compressed material.Advantageously, an amount of additive is added to the powder intendedfor compression which is such that for a punch diameter of 8 mm and aninjection of 285 mg of compressed material, at the time of a maximumpressure of 10 kN at the upper punch, the maximum pressure at the lowerpunch is 92% to 98% of the maximum pressure of the upper punch.

If a quantity of additive is added to the powder intended forcompression into shaped articles which is too small, then there is arisk that the desired effect, namely a reduced cohesion of the powderparticles with respect to each other and a reduced adhesion to extrinsicsurfaces, is not sufficient, with the consequence that the compressedmaterial could stop flowing even when it is being fed to the compressionsite, the pressing tools could be blocked by sticking particles or therequired pressure could still be so high that the shaped articlesobtained dissolve too slowly under physiological conditions, and so thesubstance would not be taken up quickly enough and the pharmaceuticaleffect would not occur. On the other hand, too large a quantity ofadditive could result in the shaped articles obtained by compression nothaving the hardness required for pharmaceuticals, and so might break up,which is undesirable, or abrade too much, which would lead tounacceptable variations in the targeted uniform active ingredientcontent of the shaped article. Thus, advantageously and desirably, thequantity of additive which is added to the powder intended forcompression is measured correctly. This can be established on the basisof the resulting properties of the shaped article, which preferablyexhibit no breakage under a linear effective force of up to 100 N,preferably up to 150 N and particularly preferably up to 200 N. In orderto determine the breaking strength, the linear effective force isrespectively applied to 10 shaped articles and the average value isdetermined. Furthermore, the abrasion is determined: in accordance withthe European Pharmacopoeia, issue 8.0, a number of shaped articles witha total weight of as close to 6.5 g as possible are placed in a rotatingdrum after they have been carefully freed from any abraded material ordust already present. The drum is then rotated 100 times at a speed of25 revolutions per minute. Next, the shaped articles are carefully freedfrom abraded material and dust once again, weighed and the averageweight which is determined is compared with the starting weight. It hasbeen shown to be advantageous for the weight loss by dust using thisprocedure to be no more than 0.02% to 0.25% by weight.

Finally, according to the European Pharmacopoeia, issue 8.0, the shapedarticles in accordance with the invention should advantageously have adisintegration time of 2 to 4 minutes. In this regard, in each case 6shaped articles, each placed in separate baskets, are placed in 100 mLof purified water, aqua purificata, which has been heated to atemperature of 37° C. (±2° C.). The baskets are then moved 53 to 57 mmback and forth, 29 to 32 times per minute, and at predetermined timesthe disintegration status of the shaped articles and baskets removedfrom the water is assessed in accordance with the EuropeanPharmacopoeia, issue 8.0.

The invention will now be illustrated with the aid of an example of theadditive in accordance with the invention, the compressed material inaccordance with the invention, the process in accordance with theinvention and the shaped articles in accordance with the invention.

PG(3)-C22 partial esters with a hydroxyl value of 138 were firstlymicronized using supercritical fluid technology, abbreviated to “SCFT”,using carbon dioxide as the fluid; the median particle size for all ofthe particles was 13.15 μm (±0.05 μm). A proportion of these particleswas used as an additive. The pharmaceutical substance was metformin-HCl;the filler was microcrystalline cellulose, known by the trade nameAvicel PH102. Prior to mixing, the metformin-HCl was passed through asieve with a pore size of 200 μm. In this example, the powder wastherefore a mixture of metformin-HCl and microcrystalline cellulose, theadditive was PG(3)-C22 partial ester-[138], wherein the number in squarebrackets gives the hydroxyl value here. The compressed material wasobtained by mixing these components in a Turbula TC2 mixer from Willy ABachofen Maschinenfabrik (CH) at 75 revolutions per minute for 10minutes; the compressed material consisted of 15% by weight ofmetformin-HCl, 84.75% by weight of microcrystalline cellulose and 0.25%by weight of PG(3)-C22 partial ester-[138]. The compressed material wascompressed into flat tablets in a Stylcam 200R compacting simulator fromMedelpharm (FR) using punches and dies from Natoli (USA) with a diameterof 8 mm. The subsequent investigations of the prepared tablets inaccordance with European Pharmacopoeia issue 8.0 provided adisintegration time of only 2 minutes, an abrasion of 0.12%. Thebreaking strength of the tablets was strong enough to withstand a lineareffective force of up to 140 N; the ejection force to remove the tabletsfrom the die was only 120 N.

In a second example, the composition of the compressed material wasvaried; 84.9% by weight of microcrystalline cellulose, 15% by weight ofmetformin-HCl and 0.1% by weight of a blend of equal parts of PG(3)-C22full ester and PG(3)-C22 partial ester-[138] were compressed. For thisexample, the disintegration time was 4 minutes, the abrasion was only0.02%, the breaking strength of the tablets was strong enough towithstand a linear effective force of up to 200 N and the ejection forcerequired was 175 N.

The investigation of the RAMAN spectra of a modified compressed materialwhich consisted of 95% metformin-HCl and 5% additive, or alternatively50% metformin-HCl and 50% additive, compared with the RAMAN spectra ofthe individual components and compared with the RAMAN spectra of thetablets prepared from it, indicated that there were no interactions orincompatibilities between the additive and the pharmaceutical substance,even after storage of the tablets for one month at 40° C. The variationin the composition of the compressed material compared with thepreceding example was made in order to provoke any opposing influencesof the components before, during and after compression by leaving outthe filler and to make them more noticeable.

The properties of some PGFEs will now be illustrated by way of exampleand with the aid of the figures.

The partial ester PG(4)-C18 had the quantitative main structure shown inFIG. 1, when investigated using gas chromatography linked with massspectroscopy (GC-MS).

FIG. 2 shows the results of the investigation of PG(4)-C18 usingdifferential scanning calorimetry, wherein the temperature values are onthe X axis of the diagram and the heat flux in mW/g is on the Y axis.The left hand diagram in FIG. 2 shows two almost coincident curves fortwo measurements of the partial ester PG(4)-C18, which each exhibitprecisely one endothermic minimum which can be assigned to theenergy-consuming transition from the solid to the liquid phase uponmelting of the partial ester. The right hand diagram for the partialester PG(4)-C18 in FIG. 2 shows precisely one exothermic maximum whichcan be assigned to the energy-releasing transition from the liquid tothe solid phase upon solidification of the partial ester. Themeasurements were carried out using a DSC 204 F1 Phoenix from NietzschGerstebau GmbH, 95100 Selb, Germany. In this regard, a sample of 3-4 mgwas weighed into an aluminium crucible and the heat flux wascontinuously recorded at a heating rate of 5K per minute. A second runwas carried out using the same heating rate.

FIG. 3 shows, as a contrast to the desired behaviour of the polyglycerolfatty acid ester, the typical behaviour of a polymorphic triacylglycerol during an investigation using differential scanning calorimetryand upon heating up. Here, two local endothermic minima with anintermediate exothermic maximum can be seen, wherein the firstendothermic minimum on the left hand side is due to melting of theunstable a-modification followed by the exothermic maximum uponcrystallization to form the more stable b-modification, which in turnmelts as the temperature rises further, as can be seen by the secondlocal endothermic minimum on the right hand side.

FIG. 4 shows the PG(4)-C18 partial ester investigated using differentialscanning calorimetry upon heating up, after storage for 6 months at roomtemperature. FIG. 5 shows the PG(4)-C18 partial ester investigated usingdifferential scanning calorimetry, upon heating up after storage for 6months at 40° C. In both cases, as before, there is no exothermicmaximum which could indicate crystallization into a more stablemodification.

For the WAXS and the SAXS analyses, a spot focusing camera system,S3-MICRO, formerly Hecus X ray Systems Gesmbh, 8020 Graz, Austria, nowBruker AXS GmbH, 76187 Karlsruhe, Germany, was equipped with two linearposition-sensitive detectors with a resolution of 3.3-4.9 Angstroms(WAXS) and 10-1500 Angstroms (SAXS). The samples were introduced into aglass capillary with a diameter of approximately 2 mm, which was thensealed with wax and placed in the rotary capillary unit. The individualmeasurements were made at room temperature by exposure to a beam of Xrays at a wavelength of 1.542 Angstroms for 1300 sec.

FIG. 6 shows the results of the WAXS analysis for different polyglycerolfatty acid esters including PG(4)-C18 partial ester (labelled) belowtheir solidification temperature, which all exhibit an intensity maximumat a 20 of 21.4°. The Bragg angle corresponds to a separation of thelattice planes of 415 μm, which is typical for the lamellar packing ofthe a-modification. The maximum intensity was stable both after storagefor 6 months at room temperature, as can be seen in FIG. 7, and alsoafter storage for 6 months at 40° C., as can be seen in FIG. 8.

FIG. 9 shows the results of the SAXS analysis for various polyglycerolfatty acid esters. For PG(4)-C18 partial ester, a lamellar separation of65.2 Angstroms could be derived. The thickness of the crystallites,calculated from the Scherrer equation, was 12.5 nm with a Scherrerconstant of 0.9, a wavelength of 1.542 Angstroms, a FWHM value of 0.0111and a Bragg angle 9 of 0.047 (radians). The values for the SAXS analysisof PG(4)-C18 partial ester remained the same even after storage for sixmonths, both at room temperature and also at 40° C. (not shown).

The analysis from the differential scanning calorimetry also enabledpredictions to be made about the solidification temperature of thePG(4)-C18 partial ester. The peak of the exothermic maximum upon coolingthe sample down was between 53.4° C. and 57.0° C. with the maximum at55.2° C., which marks the solidification temperature.

FIG. 10 shows a diagram illustrating the measurement of the contactangle (see para [0020]). For PG(4)-C18 partial esters, the contact angleis approximately 84°, which correlates to a HLB value of approximately5.2. Compared with other polyglycerol fatty acid esters, PG(4)-C18partial esters can be assigned to the hydrophilic polyglycerol fattyacid esters, as can be seen in FIG. 11 (here=PG4-C18). FIG. 12 shows thevariation in contact angle for PG(4)-C18 partial esters, see centralgraph, against the start measurement (left hand column), after 16 weeksat room temperature (central column) and after 16 weeks at 40° C. (righthand column). The contact angle varied by no more than 10°, and so thehydrophobicity can be described as stable compared with monoglycerolfatty acid esters such as tristearyl glycerol, for example. This is alsothe case for the PG3-C16/C18 partial ester also shown in FIG. 12, lefthand graph, and PG6-C18 partial esters, right hand graph.

1. An additive for influencing the cohesion and lubrication on extrinsicsurfaces of a powder provided for mechanical compression into shapedarticles and consisting of particles, characterized by one or morepolyglycerol fatty acid esters as the main component, respectivelyobtainable from a complete or partial esterification of a linear orbranched polyglycerol containing two to eight glyceryl units with one ormore fatty acids each containing 6 to 22 carbon atoms.
 2. The additiveas claimed in claim 1, characterized in that the fatty acids on whichthe polyglycerol fatty acid ester or polyglycerol fatty acid esters arebased are saturated or unbranched or both saturated as well asunbranched.
 3. The additive as claimed in claim 1, characterized in thatthe fatty acids on which the polyglycerol fatty acid ester orpolyglycerol fatty acid esters are based contain 16, 18, 20 or 22 carbonatoms.
 4. The additive as claimed in claim 1, characterized in that aninvestigation of the individual polyglycerol fatty acid ester orpolyglycerol fatty acid esters using heat flux differential scanningcalorimetry produces, upon heating up, respectively only one endothermicminimum and upon cooling down, respectively only one exothermic maximum.5. The additive as claimed in claim 1, characterized in that thepolyglycerol fatty acid ester or polyglycerol fatty acid esters have astable subcellular form below the solidification temperature with alamellar separation over at least 6 months at 40° C. which issubstantially constant according to an evaluation of the Bragg angledetermined by WAXS analysis.
 6. The additive as claimed in claim 1,characterized in that the polyglycerol fatty acid ester or polyglycerolfatty acid esters have a stable subcellular form below thesolidification temperature with a substantially constant thickness ofthe lamellar-structured crystallites over at least 6 months at 40° C.according to SAXS analysis evaluated using the Scherrer equation.
 7. Theadditive as claimed in claim 1, characterized by at least onepolyglycerol fatty acid ester from the following group: PG(2)-C18 fullesters, PG(2)-C22 partial esters with a hydroxyl value of 15 to 100,PG(2)-C22 full esters, PG(3)-C16/C18 partial esters with a hydroxylvalue of 100 to 200, PG(3)-C22 partial esters with a hydroxyl value of100 to 200, PG(3)-C22 full esters, PG(4)-C16 partial esters with ahydroxyl value of 150 to 250, PG(4)-C16 full esters, PG(4)-C16/C18partial esters with a hydroxyl value of 150 to 250, PG(4)-C16/C18 fullesters, PG(4)-C18 partial esters with a hydroxyl value of 100 to 200,PG(4)-C22 partial esters with a hydroxyl value of 100 to 200,PG(6)-C16/C18 partial esters with a hydroxyl value of 200 to 300,PG(6)-C16/C18 full esters, PG(6)-C18 partial esters with a hydroxylvalue of 100 to 200, wherein in the polyglycerol fatty acid esterscontaining two fatty acid residues which are different because of thenumber of their carbon atoms, those with a lower number are present inan amount of 35% to 45%, those with a corresponding, complementaryhigher number are present in an amount of 55% to 65% and the specifiedfull esters preferably have a hydroxyl value of less than
 5. 8. Theadditive as claimed in claim 1, characterized in that the polyglycerolfatty acid ester or individual polyglycerol fatty acid esters have asolidification temperature of below 75° C. and above 40° C.
 9. Theadditive as claimed in claim 1, characterized in that the contact angleof the polyglycerol fatty acid ester or individual polyglycerol fattyacid esters during the determination of the hydrophobicity differs byless than 10° from the starting value after 16 weeks at 40° C. as wellas at 20° C.
 10. The additive as claimed in claim 1, characterized bypost-synthesis mixing of polyglycerol fatty acid esters which arerespectively obtainable from esterification reactions which aredifferent because different reaction partners are used or becausedifferent reaction conditions are employed.
 11. The additive as claimedin claim 1, characterized in that the median of the diameter of theparticle is 1 μm to 300 μm, preferably 5 μm to 15 μm.
 12. Compressedmaterial from an additive as claimed in claim 1, and a powder as claimedin claim 1, characterized in that the proportion of additives is no morethan 5% by weight, preferably 0.05% to 0.5% by weight.
 13. Compressedmaterial as claimed in claim 12, characterized in that the powdercontains a pharmaceutical substance.
 14. The compressed material asclaimed in claim 12, characterized in that the powder containsmicrocrystalline cellulose.
 15. The compressed material as claimed inclaim 12, characterized by 0.05% to 0.5% by weight of additive and 99.5%to 99.95% by weight of powder, wherein the additive consists of amixture of respectively 50% by weight of PG(3)-C22 full ester andPG(3)-C22 partial ester with a hydroxyl value of 100 to 200 or entirelyof PG(3)-C22 partial ester with the same hydroxyl value.
 16. Thecompressed material as claimed in claim 12, characterized by aproportion of 15% by weight of metformin-HCl and a proportion of 84.5%to 84.95% by weight of microcrystalline cellulose.
 17. The compressedmaterial as claimed in claim 12, characterized by the property, for acompressed material weight of 285 mg in a cylindrical die with adiameter of 8 mm, of transferring 90% to 99% of the maximum pressingforce of 10 kN at the upper punch of a rotary press onto the lowerpunch.
 18. A process for the preparation of a shaped article from apowder by mechanical compression, characterized in that prior tocompression, an additive as claimed in claim 1, is added to the powder,preferably prior to feeding to the compression site.
 19. Shapedarticles, preferably tablets, produced by mechanical compression in adie, characterized by a composition identical to that of the compressedmaterial as claimed in claim
 12. 20. The shaped articles as claimed inclaim 19, characterized in that the force which is necessary to ejectthe shaped article from the die under otherwise identical conditions isno more than 150% of the ejection force for a test shaped article forwhich at least 40% by weight of the additive has been replaced by MgStand the remainder optionally by the filler employed, preferablymicrocrystalline cellulose.
 21. The shaped articles as claimed in claim19, characterized by a breaking strength under a linear effective forceof up to 150 N, preferably up to 200 N and particularly preferably up to250 N.
 22. The shaped articles as claimed in claim 19, characterized byan abrasion of 0.02% to 0.25% by weight, determined in accordance withthe European Pharmacopoeia, issue 8.0.
 23. The shaped articles asclaimed in claim 19, characterized by a disintegration time of 2 to 4minutes, tested in accordance with the European Pharmacopoeia, issue8.0.